hbv-dna detection by hybridization assay in the serum of anti-hbe positive hbv carriers hbv-dna +...
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HBV-DNA detection by hybridization assay in the serum of anti-HBe positive HBV carriers
HBV-DNA + Chronic Hepatitis
11/19 58% 11/14 79% Bonino 1980 7/13 54% - Scotto 198316/32 50% - Liebermann 198314/24 58% 14/18 78% Hadziyannis 198328/106 26% 28/46 65% Bonino 1984 8/30 27% 8/21 38% Lok 198410/153 7% 1/5 20% Tur Kaspa 198414/78 18% 10/38 26% Wu 1986
116/455 25% 72/139 52%
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Chronic anti-HBe positive hepatitis B was born in 1980 in the Mediterranean area
< 2% - Low 2-7% - Intermediate > 8% - High
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Chronic anti-HBe positive hepatitis B
FeaturesFeatures
Virological :Virological : mean viremia levels lower than those observed in HBeAg positive patients
Clinical:Clinical: progressive liver disease with low rate of spontaneous resolutions, in spite of temporary remissions
high relapse rate after the end of IFN, in spite of the response obtained during treatment
Brunetto MR, Hepatology 1989
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HBeAg positive infection
Anti-HBe positive infection
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Identification of 1896 G to A switch as causative agent of
anti-HBe positive chronic hepatitis B
Brunetto MR et al, Ital. J Gastro 1989Carman A et al, Lancet 1989Santantonio T et al, Virology 1991
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NUCLEOCAPSID PROTEINS: HBeAg
PRE-C CORE
183 aa
E.R.
29 aa
149 (154) aa10 aa
17 kDa non particulate, secreted HBeAg
Substitution of 7cys restores particle formation and HBcAg antigenicity
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Hepatitis B Virus
Li J-S et al, J Virol 1993
Sequence ofpre-core codon 15 Genotype
Size of gene(nucleotides)
core Pre-S
CCC
CCU
CCC/U
CCU
CCU
CCC/U
A
B
C
D
E
F
555
549
549
549
549
549
519
519
519
486
486
486
BestBestmatchingmatchingwithwithcodon 28codon 28
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Genotype D is the prevailing HBV genotype inthe Mediterranean area where Chronic anti-
HBe positive hepatitis B was originally described
< 2% - Low 2-7% - Intermediate > 8% - High
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Reports from South Europe on the various features, the outcome and response to IFN of HBeAg negative/anti-HBe positive CHB, mainly concern 1896 GtoA ,genotype D CHB and do not necessarily apply to other geographical areas where other virologicform of HBeAg-negative CHB may prevail
Hadziyannis SJ, J Hep 2002
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Modulation of HBeAg expression
Transcriptional
Translational
Basic core promoter mutants
HDV super/co-infections
Pre-core mutants:1896 G to A Stop at codon 281817 C to T Stop at codon 21897 G to A Stop at codon 281816 G to T Elimination of1815 T to C start codon 1
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Anti-HBe positive chronic hepatitis B: 1896 G to A switch by oligohybridization
assay
All patients were of Italian origin
52 (31.7%)52 (31.7%)
99 (60.4%)99 (60.4%)
13 (7.9 %)13 (7.9 %)
161 / 164 (98.2%)
Brunetto MR,1999
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Anti-HBe positive chronic hepatitis B: pre-core heterogeneity by direct sequencing in 18 patients from Tuscany
1762 1764 1896 1899 A - T G - A G - A G - A
12/18 12/18 11/18 6/18
66.6% 66.6% 61.1% 33.3%
+ + - - in 5 patients
- - - - in 2 patients
Moscato G, 2001
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HBeAg+ 9%
anti-HCV+ 6%
anti-D+/ anti-HCV+
1%
anti-HBe+ 77%
anti-D+ 7%
Gaeta et al. Year of analisys:1997
Chronic HBsAg Hepatitis in ItalyChronic HBsAg Hepatitis in Italy834 cases in 14 centres834 cases in 14 centres
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89%
11%
42%58%
HBeAg pos.veHBeAg pos.ve anti-HBe pos.veanti-HBe pos.veCases = 538Cases = 538 Cases = 718Cases = 718
Giusti et al.Giusti et al.1975-851975-85
Gaeta et al.Gaeta et al.19971997
Change of HBeAg and anti-HBe Distribution in positive HBsAg Carriers in Italy
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Chronic anti-HBe positive hepatitis B
Reasons for the increase of its prevalence in Italy:Reasons for the increase of its prevalence in Italy:
- reduction of HBeAg positive cases
- long lasting unresolving disease inducing a progressive accumulation of cases in the population
- increase in the diagnostic accuracy (more sensitive assays, more diagnostic accuracy by the clinicians)
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Geographic Distribution of HBsAg Carriers
< 2% - Low 2-7% - Intermediate > 8% - High
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Chronic anti-HBe positive hepatitis B
Reasons for the increase of its prevalence in Italy:Reasons for the increase of its prevalence in Italy:
- reduction of HBeAg positive cases
- long lasting unresolving disease inducing a - long lasting unresolving disease inducing a progressive accumulation of cases in the populationprogressive accumulation of cases in the population
- increase in the diagnostic accuracy (more sensitive assays, more diagnostic accuracy by the clinicians)
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Outcome of Chronic Anti-HBe Positive Hepatitis B
0 10 20 30 40 50 60 70 80
INFECTION
36 - 40 y.Age (years)
45 y.
CIRRHOSIS
asymptomatic
HBeAg minus selection
High intrafamiliar infection (43.9%) Low parenteral exposure (13.4%)Small number of patients with history of acute hepatitis (4.8%) or HBeAg pos. (2.4%)
High rate of asymptomaticcarriers among relativesHigh rate of acute hepatitis in sexual partners
DIAGNOSIS
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Outcome of chronic anti-HBe positive hepatitis B
Steadyness
Amelioration
Cirrhosis
4 Signs of portal hypertension2 Died1 OLT
Worsening
Cirrhosis
Steadyness
2nd Biopsy 63/8772.4%
102 patients (mean age 36 y) with chronic hepatitis at histology Median follow-up 6y. (mean 5.9y.; range 2-12y.)
Biochemicaland ClinicalOutcome
85.3%
7.8% 6.9%
38.1%
49.2%
12.7%
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50 50
Hepatitis Healthy
80
20
Hepatitis Healthy
80
20
Hepatitis Healthy
Gaeta et al. 2000
20 years old 50 years old
Prevalence of Chronic anti-HBe positive
Hepatitis B by Age
% %
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Chronic anti-HBe positive hepatitis B
Reasons for the increase of its prevalence in Italy:Reasons for the increase of its prevalence in Italy:
- reduction of HBeAg positive cases
- long lasting unresolving disease inducing a progressive accumulation of cases in the population
- increase in the diagnostic accuracy - increase in the diagnostic accuracy (more sensitive assays, more diagnostic(more sensitive assays, more diagnostic accuracy by the clinicians) accuracy by the clinicians)
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Outcome of Chronic Anti-HBe Positive Hepatitis B
0
100
200
300
400
0
100
200
300
400
0
100
200
300
400
Biochemical patterns in 164 untreated patientsafter 23 months (range 12-36) monthly monitoring
0 12 24months
With flares and normalization
Without flares
With flares and without normalization
73 pts ( 44.5% )
59 pts ( 36.0% )
32 pts ( 19.5% )
Asymptomatic flare-up:
90% of cases
ALT Flare-up yearly
frequency:once 57.1%twice 20%
< once 22.8%
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Viremia profilepersistently > 106 gen/ml 15 ( 9.1%)occasionally < 106 gen/ml 52 (31.7%)frequently < 106 gen/ml 87 (53.1%)persistently < 106 gen/ml 10 ( 6.3%)
IgM anti-HBc profile
persistently > 7 PEI I.U. 110 (67.1%) 57.9% 82.2%fluctuations < 7 PEI I.U. 54 (32.9%) 42.1% 17.8% fluctuations < 4 PEI I.U. 5 ( 3.0%)
ALL ChronicHepatitis Cirrhosis
2 9.332, p = 0.002
Anti-HBe positive chronic hepatitis B: virological patterns in 164 patients 23 months (range 12-36) monthly monitoring
Brunetto MR,1999
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A favoring condition due to the changed HBV epidemiology in Italy
A better understanding of what we are looking for and how to do it
Are the major factors responsible for the increased prevalence of anti-HBe positive CHB in Italy
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AKNOWLEDGEMENT
Anna Maria Maina Giovanna Moscato
Filippo Oliveri Barbara Coco
Piero Colombatto Ferruccio Bonino